Na+/Ca2+ exchanger isoform 1 takes part to the Ca2+-related prosurvival pathway of SOD1 in primary motor neurons exposed to beta-methylamino-l-alanine

Background The cycad neurotoxin beta-methylamino-l-alanine (L-BMAA), one of the environmental trigger factor for amyotrophic lateral sclerosis/Parkinson-dementia complex (ALS/PDC), may cause neurodegeneration by disrupting organellar Ca2+ homeostasis. Through the activation of Akt/ERK1/2 pathway, the Cu,Zn-superoxide dismutase (SOD1) and its non-metallated form, ApoSOD1, prevent endoplasmic reticulum (ER) stress-induced cell death in motor neurons exposed to L-BMAA. This occurs through the rapid increase of intracellular Ca2+ concentration ([Ca2+]i) in part flowing from the extracellular compartment and in part released from ER. However, the molecular components of this mechanism remain uncharacterized. Methods By an integrated approach consisting on the use of siRNA strategy, Western blotting, confocal double- labeling immunofluorescence, patch-clamp electrophysiology, and Fura 2-/SBFI-single-cell imaging, we explored in rat motor neuron-enriched cultures the involvement of the plasma membrane proteins Na+/Ca2+ exchanger (NCX) and purinergic P2X7 receptor as well as that of the intracellular cADP-ribose (cADPR) pathway, in the neuroprotective mechanism of SOD1. Results We showed that SOD1-induced [Ca2+]i rise was prevented neither by A430879, a P2X7 receptor specific antagonist or 8-bromo-cADPR, a cell permeant antagonist of cADP-ribose, but only by the pan inhibitor of NCX, CB-DMB. The same occurred for the ApoSOD1. Confocal double labeling immunofluorescence showed a huge expression of plasmalemmal NCX1 and intracellular NCX3 isoforms. Furthermore, we identified NCX1 reverse mode as the main mechanism responsible for the neuroprotective ER Ca2+ refilling elicited by SOD1 and ApoSOD1 through which they promoted translocation of active Akt in the nuclei of a subset of primary motor neurons. Finally, the activation of NCX1 by the specific agonist CN-PYB2 protected motor neurons from L-BMAA-induced cell death, mimicking the effect of SOD1. Conclusion Collectively, our data indicate that SOD1 and ApoSOD1 exert their neuroprotective effect by modulating ER Ca2+ content through the activation of NCX1 reverse mode and Akt nuclear translocation in a subset of primary motor neurons.

Biosynthesis of Antibacterial Iron-Chelating Tropolones in Aspergillus nidulans as Response to Glycopeptide-Producing Streptomycetes

The soil microbiome comprises numerous filamentous fungi and bacteria that mutually react and challenge each other by the production of bioactive secondary metabolites. Herein, we show in liquid co-cultures that the presence of filamentous Streptomycetes producing antifungal glycopeptide antibiotics induces the production of the antibacterial and iron-chelating tropolones anhydrosepedonin (1) and antibiotic C (2) in the mold Aspergillus nidulans. Additionally, the biosynthesis of the related polyketide tripyrnidone (5) was induced, whose novel tricyclic scaffold we elucidated by NMR and HRESIMS data. The corresponding biosynthetic polyketide synthase-encoding gene cluster responsible for the production of these compounds was identified. The tropolones as well as tripyrnidone (5) are produced by genes that belong to the broad reservoir of the fungal genome for the synthesis of different secondary metabolites, which are usually silenced under standard laboratory conditions. These molecules might be part of the bacterium-fungus competition in the complex soil environment, with the bacterial glycopeptide antibiotic as specific environmental trigger for fungal induction of this cluster.

The Role of Fecal Microbiota Transplantation in the Treatment of Inflammatory Bowel Disease

The exact pathogenesis of inflammatory bowel disease (IBD) is still not completely understood. It is hypothesized that a genetic predisposition leads to an exaggerated immune response to an environmental trigger, leading to uncontrolled inflammation. As there is no known causative treatment, current management strategies for inflammatory bowel disease focus on correcting the excessive immune response to environmental (including microbial) triggers. In recent years, there has been growing interest in new avenues of treatment, including targeting the microbial environment itself. Fecal microbiota transplantation (FMT) is a novel treatment modality showing promising results in early studies. The article discusses the rationale for the use of FMT in inflammatory bowel disease and the yet-unresolved questions surrounding its optimal use in practice.

A Review of the Environmental Trigger and Transmission Components for Prediction of Cholera

Climate variables influence the occurrence, growth, and distribution of Vibrio cholerae in the aquatic environment. Together with socio-economic factors, these variables affect the incidence and intensity of cholera outbreaks. The current pandemic of cholera began in the 1960s, and millions of cholera cases are reported each year globally. Hence, cholera remains a significant health challenge, notably where human vulnerability intersects with changes in hydrological and environmental processes. Cholera outbreaks may be epidemic or endemic, the mode of which is governed by trigger and transmission components that control the outbreak and spread of the disease, respectively. Traditional cholera risk assessment models, namely compartmental susceptible-exposed-infected-recovered (SEIR) type models, have been used to determine the predictive spread of cholera through the fecal–oral route in human populations. However, these models often fail to capture modes of infection via indirect routes, such as pathogen movement in the environment and heterogeneities relevant to disease transmission. Conversely, other models that rely solely on variability of selected environmental factors (i.e., examine only triggers) have accomplished real-time outbreak prediction but fail to capture the transmission of cholera within impacted populations. Since the mode of cholera outbreaks can transition from epidemic to endemic, a comprehensive transmission model is needed to achieve timely and reliable prediction with respect to quantitative environmental risk. Here, we discuss progression of the trigger module associated with both epidemic and endemic cholera, in the context of the autochthonous aquatic nature of the causative agent of cholera, V. cholerae, as well as disease prediction.

The resident TP712 prophage of Lactococcus lactis MG1363 provides extra holin functions to the new P335 phage CAP for effective host lysis

Prophages are widely present in Lactococcus lactis , a lactic acid bacterium (LAB) that plays a key role in dairy fermentations. L. lactis MG1363 is a laboratory strain used worldwide as a model LAB. Initially regarded as plasmid- and prophage-free, MG1363 carries two complete prophages TP712 and MG-3. Only TP712 seems to be inducible but unable to lyse the host. Several so-called TP712 lysogens able to lyse upon prophage induction were reported in the past, but the reason for their lytic phenotype remained unknown. In this work, we describe CAP, a new P335 prophage detected in the “lytic TP712 lysogens”, which had remained unnoticed. CAP is able to excise after mitomycin C treatment, along with TP712, and able to infect L. lactis MG1363-like strains but not the lytic TP712 lysogens. Both phages cooperate for efficient host lysis. While the expression i n trans of the CAP lytic genes was sufficient to trigger cell lysis, this process was boosted when the resident TP712 prophage was concomitantly induced. Introduction of mutations into the TP712 lytic genes revealed that its holin but not its endolysin plays a major role. Accordingly, it is shown that the lytic activity of the recombinant CAP endolysin relies on membrane depolarization. Revisiting the seminal work to generate the extensively used L. lactis MG1363 strain led us to conclude that the CAP phage was originally present in its ancestor L. lactis NCDO712 and our results solved long-standing mysteries around the MG1363 resident prophage TP712 reported in the “pre-sequencing” era. Importance Prophages are bacterial viruses that integrate in the chromosome of bacteria until an environmental trigger induces their lytic cycle ending with lysis of the host. Prophages present in dairy starters can compromise milk fermentation and represent a serious threat in dairy plants. In this work, we have discovered that two temperate phages TP712 and CAP infecting the laboratory strain Lactococcus lactis MG1363 join forces to lyse the host. Based on the in vitro lytic activity of the LysCAP endolysin, in combination with mutated versions of TP712 lacking either its holin or endolysin, we conclude that this cooperation relies on the combined activity of the holins of both phages that boost the activity of LysCAP. The presence of an additional prophage explains the lytic phenotype of the formerly thought to be single TP712 lysogens that had remained a mystery for many years.

A Case Report on Kawasaki Disease

Kawasaki disease is a vascular and self-limiting disease mainly effecting small to medium sized vessel. Mostly affecting the children of less than 5 years. Most of the patients has a genetic predisposition. Genetically susceptible individuals exposed to infectious agents/ environmental trigger may develop Kawasaki disease. Clinical presentations are fever, polymorphous rashes along the trunk, strawberry tongue, swollen lymph nodes around neck. Skin of palms and soles can be swollen and red. Lips are cracked, red and dry. A 7 year old male patient was brought to emergency department with Scarlett fever, dry lips, Thickening of palmar skin, Itching. Patient was shifted to pediatrics department and was provided with adequate treatment. Keywords: Kawasaki disease, Genetically susceptible, Strawberry tongue, polymorphous rashes.

Epidemiology of Kawasaki Disease in Europe

Aim of the review: To review major epidemiological aspects of Kawasaki disease (KD) in Europe, describing demographic characteristics, revising its incidence along with time trends and geographic variations, and describing migration studies to provide clues about its etiology.Recent findings: The annual incidence of KD in Europe is about 10–15 per 100,000 children under 5 years old and seems to be relatively stable over time and space. Demographic characteristics are in line with those in other countries of the world, with a higher incidence in children from Asia and possibly North African origin. All studies performed across Europe found a coherent seasonal distribution of KD onset peaking from winter to early spring. This seasonal distribution was consistent over the years and suggests a climate-related environmental trigger. The occurrence of peaks during pandemics, microbiological findings and a possible link with southerly winds support the hypothesis of an airborne infectious agent. Neither other airborne agents such as pollutants or pollens nor urbanization and industrialization seem to have major effect on the etiology.Conclusion: Discrepancies in KD incidence rates across studies were due more to methodological differences, variation in definitions and awareness of the disease than a real increase in incidence. Genetic predisposition is undeniable in KD, but environmental factors seem to play a pivotal role. Several lines of evidence support a non-exclusive airborne infectious agent with a protective immune response by the host as a key factor in inducing the inflammatory cascade responsible for symptoms and complications.

Acceptability and Perceived Utility of Virtual Reality among People who are Incarcerated who use Drugs: A Qualitative Study (Preprint)

UNSTRUCTURED Virtual reality (VR) allows a platform to create common scenarios of environmental trigger situations to elicit drug cravings. We know little about acceptability of VR among people who are incarcerated who use drugs. Mixed methods explored VR perspectives and stress response among 20 inmates with a substance use disorder at a county jail. Cardiovascular data were collected to determine if exposure to the VR environment provoked a stress response. Repeated measures mixed models were used to assess stress reactivity measured by three heart rate variability indices (HR, RMSSD, and HF-HRV). Qualitative interviews assessed acceptability and perceived utility on VR in the jail setting. Cardiovascular data analyses showed no significant increase in stress reactivity for HR (b = -3.14, t(18) = -3.85, p < .01 ), RMSSD (b = -0.06, t(18) = -1.06, p = 0.30 ) and HF-HRV (b = -0.21, t(18) = -1.71, p = 0.10). Qualitative data indicate high levels of acceptability and potential utility in the following thematic areas: (1) mental health and substance use interventions; (2) community re-entry skills training; and (3) communication and conflict resolution skills. Results demonstrated high acceptability and no significant stress response of VR among people who are incarcerated who use drugs.

A Review and Roadmap of the Skin, Lung, and Gut Microbiota in Systemic Sclerosis

As our understanding of the genetic underpinnings of systemic sclerosis (SSc) increases, questions regarding the environmental trigger(s) that induce and propagate SSc in the genetically predisposed individual emerge. The interplay between the environment, the immune system, and the microbial species that inhabit the patient’s skin and gastrointestinal tract is a pathobiological frontier that is largely unexplored in SSc. The purpose of this review is to provide an overview of the methodologies, experimental study results, and future roadmap for elucidating the relationship between the SSc host and his/her microbiome.

Differential serum interferon-β levels in autoimmune thyroid diseases

IntroductionInterferon (IFN)-β is known as an environmental trigger for the occurrence of autoimmune thyroid disease (AITD). However, the association of another type-1 IFN, IFN-β, with AITD is unknown.Material and methodsIn the study, we explored the association of serum IFN-β levels with AITD in an ethnic Chinese (i.e., Taiwanese) population. We enrolled 160 patients with Graves’ disease (GD), 47 patients with Hashimoto’s thyroiditis (HT), and 119 healthy controls. Serum IFN-β and B-cell activating factor (BAFF) levels were quantified in healthy controls at the baseline and in patients with AITD either prior to receiving medication or while under medication. Thyroid function and thyroid-stimulating hormone receptor antibody (TSHRAb) levels were measured at the time of serum collection.ResultsSerum IFN-β levels were lower in the HT group than in the control group (p = 0.031). A significant inverse correlation was observed between IFN-β and TSHRAb levels in men with GD (r = –0.433, p = 0.044). Serum IFN-β levels were also negatively associated with BAFF levels in men with GD, HT, and AITD (r = –0.320, p = 0.032; r = –0.817, p = 0.047; and r = –0.354, p = 0.011, respectively), but not in women with GD, HT, or AITD.ConclusionsSerum IFN-β levels were lower in HT patients. Correlations of serum IFN-β with TSHRAb and BAFF levels were found to be gender-specific. Further well-designed studies with larger sample sizes are required to confirm our findings.